A proteasome inhibitor, an antioxidant, or a salicylate, but not a glucocorticoid, blocks constitutive and cytokine-inducible expression of P-selectin in human endothelial cells.
Proteasome inhibitors, antioxidants, salicylates, or glucocorticoids block the cytokine-induced expression of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. These pharmacological agents have been assumed to inhibit the expression of adhesion molecules primarily by blocking activation of the transcription factor NF-kappaB. We found that the proteasome inhibitor ALLN, the antioxidant PDTC, or sodium salicylate, but not the glucocorticoid dexamethasone, inhibited both the constitutive and the interleukin-4- or oncostatin M-induced expression of the adhesion molecule P-selectin in human endothelial cells. ALLN, PDTC, or sodium salicylate decreased P-selectin expression without a detectable requirement for inhibition of NF-kappaB activation or for an intact kappaB element in the P-selectin gene. These results extend the potential anti-inflammatory utility of such drugs to inhibition of P-selectin expression and suggest that they have important actions that do not involve the NF-kappaB system.
Xia
L
L
W.K. Warren Medical Research Institute, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Pan
J
J
Yao
L
L
McEver
R P
RP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D053683:Oncostatin M; D019007:P-Selectin / Q000235:genetics*; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012980:Sodium Salicylate / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology; D014471:Umbilical Veins
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D007976:Leupeptins; D016328:NF-kappa B; C508351:OSM protein, human; D019007:P-Selectin; D010455:Peptides; D011759:Pyrrolidines; D013859:Thiocarbamates; D053683:Oncostatin M; C063261:acetylleucyl-leucyl-norleucinal; D015847:Interleukin-4; C020972:pyrrolidine dithiocarbamic acid; D003907:Dexamethasone; D012980:Sodium Salicylate